title: A novel compound that elevates high density lipoprotein and activates the peroxisome proliferator activated receptor.
abstract: In the current studies we describe the effects of PD 72953 and related compounds on lipoprotein levels in chow-fed male rats. After 2 weeks, 10 mg/kg of PD 72953 daily was as effective as 100 mg/kg gemfibrozil for elevating HDL-cholesterol. At 100 mg/kg, PD 72953 further elevated HDL-cholesterol to 232% of control levels, and was associated with increased HDL size and plasma apoE (169% of control), despite no change in hepatic apoE mRNA. ApoA-I rose transiently (at 1 week), but by 2 weeks only apoE remained elevated. PD 72953 dose-dependently reduced plasma apoB, VLDL-cholesterol, LDL-cholesterol, and triglyceride. Hepatic apoC-III mRNA reduction parallelled triglyceride lowering. After 1 week, 30 and 100 mg/kg per day PD 72953 reduced plasma apo-CIII levels by 30 and 34%, and triglycerides by 60 and 83%, respectively. PD 72953 treatment had no effect on triglyceride production rates; however, 125I-labeled VLDL apoB disappearance was enhanced. We compared PD 72953 to a structurally similar diacid, PD 69405, that also reduced VLDL and LDL, but had no effect on HDL elevation. Compared to PD 72953, PD 69405 further accelerated 125I-labeled VLDL apoB disappearance, decreased triglyceride production, and elevated the ratio of post-heparin hepatic to lipoprotein lipase activity. Whole animal studies, transient transfection studies in HepG2 cells, and chimeric receptor studies in kidney 293 cells suggest that PD 72953 is a ligand for the peroxisomal proliferation activated receptor alpha (PPARalpha), and PPARgamma. Overall, PD 72953 may act through a peroxisomal proliferation activated receptor and result in plasma triglycerides and apoB-containing lipoprotein reduction, while also raising HDL cholesterol. Reduced apoC-III may allow triglyceride-rich remnants to more efficiently bind and present substrate to peripheral tissue lipoprotein lipase, and therefore allow enhanced shedding of remnant phospholipid surface for HDL production.
authors.affiliation: Department of Vascular and Cardiac Diseases, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Bisgaier
authors.forename: A D
authors.initials: AD
authors.lastname: Essenburg
authors.forename: B C
authors.initials: BC
authors.lastname: Barnett
authors.forename: B J
authors.initials: BJ
authors.lastname: Auerbach
authors.forename: S
authors.initials: S
authors.lastname: Haubenwallner
authors.forename: T
authors.initials: T
authors.lastname: Leff
authors.forename: A D
authors.initials: AD
authors.lastname: White
authors.forename: P
authors.initials: P
authors.lastname: Creger
authors.forename: M E
authors.initials: ME
authors.lastname: Pape
authors.forename: T J
authors.initials: TJ
authors.lastname: Rea
authors.forename: R S
authors.initials: RS
authors.lastname: Newton
mesh_terms: D000818:Animals; D053305:Apolipoprotein C-III; D001055:Apolipoproteins B / Q000097:blood; D001056:Apolipoproteins C / Q000097:blood / Q000235:genetics; D001057:Apolipoproteins E / Q000097:blood; D002208:Caproates / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D008076:Cholesterol, HDL / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D015248:Gemfibrozil / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
chemical_list: D053305:Apolipoprotein C-III; D001055:Apolipoproteins B; D001056:Apolipoproteins C; D001057:Apolipoproteins E; D002208:Caproates; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; C111024:gemcabene; D015248:Gemfibrozil